Jiwon Lyu ¹ Drew E Narum ¹ Susan L. Baldwin ² Sasha Larsen ² Xiyuan Bai ¹ David Griffith ¹ Veronique Anne Dartois ³ Threnesan Naidoo ⁴ Adrie JC Steyn ⁵ Rhea Coler ² Edward D Chan ^1,6*

• ¹ National Jewish Health (United States), Denver, Colorado, United States
• ² Seattle Children's Research Institute, Seattle, Washington, United States
• ³ Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, United States
• ⁴ Walter Sisulu University, Mthatha, South Africa
• ⁵ Africa Health Research Institute (AHRI), Durban, South Africa
• ⁶ Rocky Mountain Regional VA Medical Center, VA Eastern Colorado Health Care System, Aurora, United States

Granulomas, organized structures derived from host immune cells in response to Mycobacterium tuberculosis (Mtb) infection, are characteristic but not exclusive of tuberculosis (TB). While there are abundant investigations on TB granulomas, the determinants that differentiate host-protective granulomas from non-protective granulomas are often unclear. Thus, the goal of this narrative review on TB granulomas is to help clarify the existing literature on such determinants. We adopt the a priori view that TB granulomas are host-protective organelles and discuss the molecular and cellular determinants that induce such protective granulomas and those that promote their failure. While reports about protective TB granulomas and their failure may initially seem contradictory, it is increasingly recognized that either deficiencies or excesses of the molecular and cellular components in TB granuloma formation may be detrimental to the host. More specifically, insufficient or excessive expression / representation of the following components have been reported to skew granulomas toward the less protective phenotype: (i) epithelioid macrophages; (ii) type 1 adaptive immune response; (iii) type 2 adaptive immune response; (iv) tumor necrosis factor; (v) interleukin-12; (vi) interleukin-17; (vii) matrix metalloproteinases; (viii) hypoxia in the TB granulomas; (ix) hypoxia inducible factor-1 alpha; (x) aerobic glycolysis; (xi) indoleamine 2,3-dioxygenase activity; (xii) heme oxygenase-1 activity; (xiii) immune checkpoint; (xiv) leukotriene A4 hydrolase activity; (xv) nuclear-factor-kappa B; and (xvi) transforming growth factor-beta. Based on these examples, a coordinated, robust, and precise immune response appears essential to effectively eradicate or at least contain Mtb infection; vis-a-vis the “Goldilocks” paradigm. Since there are several animal models of Mtb infection – whether natural (cattle, elephants) or experimental (zebrafish, mouse, guinea pig, rabbit, mini pig, goat, non-human primate) – we also compared the TB granulomatous response and other pathologic lung lesions in various animals infected with Mtb with that of human pulmonary TB. Identifying components that dictate the formation of host-protective granulomas and the circumstances that result in their failure can enhance our understanding of the macrocosm of human TB and facilitate the development of novel remedies – whether they be direct therapeutics or indirect interventions – to efficiently eliminate Mtb infection and prevent its pathologic sequelae.